The prolonged delivery of drugs orally has been a major challenge and a long desired objective in drug therapy. This is a favored route for drug administration. It is estimated that 65% of all drugs are ingested. The successful accomplishment of prolonged gastrointestinal drug delivery has great therapeutic significance in the treatment of various diseases and conditions.
Systemic and transdermal sustained drug delivery systems have been developed which are capable of delivering constant amounts of therapeutic substances from several days to several months. The major limitation to long-term oral delivery, however, is the 8-16 hour gastrointestinal transit time of an ingested substance. In order to achieve uninterrupted action for longer than 24 hours by a therapeutic substance, its passage needs to be slowed in the gastrointestinal tract or the delivery device supplying the drug has to be fixed or immobilized within the tract.
Attempts have been made either to incorporate drugs into floating devices which would empty less readily from the stomach (N. Eng. J. Med. [1981] 304:1365-1366), or to introduce balloon based devices which could be inflated by propellants or be fluid expanded in the stomach after the whole device had been swallowed. Michaels (U.S. Pat. Nos. 3,786,813; 3,788,322 and 3,901,232) proposed a series of capsular, swallowable devices. Upon ingestion, the wall of these capsules would erode, releasing a balloon support and the whole device would float in the stomach. The drug then would be released in a sustained and controlled fashion either due to the mechanical pressure exerted by a bladder on a closed drug reservoir, or dispensed from a container enclosed in a microporous membrane.
The spontaneous expulsion of such a device from the gastrointestinal tract once its active material has been expended is much more of a challenge, however. The Michaels device comes equipped with an imbedded bioerodible plug whose object is to assure the balloon's eventual deflation. In another version of the invention, the balloon loses air by being minimally permeable to a gas with which it has been inflated.
Place and Bashaw, et al disclose in U.S. Pat. Nos. 3,797,492 and 3,944,064 a variation of the system described above, suggesting that a propellant-charged capsular compartment can keep the device afloat in the stomach and also accomplish the controlled release of the active drug. Another drug-dispensing device for the prolonged administration of pharmaceuticals is disclosed in U.S. Pat. No. 4,207,890. This device is made of dual polymer envelopes, one of which swells and expands osmotically when the device reaches the stomach, while the other contains the drug and dispenses it at a predetermined determined rate based on the polymer envelope's permeability characteristics.
Yet, all these devices have major disadvantages in that they carry only a small amount of the active substance. Furthermore, as their balloon support becomes partially deflated in the stomach, this could result in their inadvertent passage into the duodenum and small intestine and produce a dangerous intestinal obstruction. Moreover, gas- or air-filled devices could burst if the individuals wearing them should travel to higher altitudes. Should the reverse occur, where an individual would travel to lower altitudes, the gas filled device could deflate.
Intragastric balloon devices have also been developed for the purpose of appetite control and weight reduction. Berman, et al (U.S. Pat. No. 4,133,315) describe a large balloon which is to be introduced deflated into the stomach via a naso-gastric tube. The balloon is to be fluid filled with an attached insufflation tube that remains in place and extends through the esophagus and the nasal passages to the outside environment. A more advanced concept of this intragastric balloon weight loss device was disclosed in U.S. Pat. No. 4,485,805. This elastomeric rubber balloon was equipped with a self-sealing valve and its inflator tube could be withdrawn from the stomach, leaving behind the fluid inflated balloon. When the desired weight loss is achieved, the balloon is to be deflated, and withdrawn from the stomach by endoscopy. Although this device was primarily developed for weight control, the inventor suggests that pharmaceuticals could also be incorporated for sustained release into the fluid used for balloon inflation.
The Garren-Edwards gastric bubble consists of a self-sealing, cylindrical intragastric balloon which has been made commercially available for weight reduction and appetite control (Endoscopy Review, 1, 57-60, 1984).
Recently, however, the phenomenon of bio or mucoadhesion with polymeric substances has received considerable attention ("Advances in Drug Delivery Systems", J. M. Anderson and S. W. Kim, Eds., Elsevier, Amsterdam, Vol. 1, 1986, pp 47-57). The temporary and adhesive attachment of prolonged release drug delivery systems to the gastrointestinal mucosa is a novel approach. However, the various mucoadhesive techniques are still under early experimental investigation.
There is clearly a need for a practical gastrointestinal drug delivery device that is relatively simple, safe to use, and is able to release significant quantities of active agent in a prolonged and controlled manner. The objective of this invention is to provide a novel device that fulfills these requirements.